Abstract

CD8+ T cells formed early in life respond more rapidly to infection, and this appears to be the result of a pre-programmed effector-like chromatin landscape.

The seeding of the immune system by distinct waves of cells during development has been described for several lineages. In this paper, Rudd and colleagues extend our understanding of the importance of developmental origin by investigating the influence of ontogeny on the CD8+ T cell lineage.

The authors developed a novel reporter system using an inducible Cre recombinase to timestamp (ts) CD4+CD8+ thymocytes. CD8+ T cells arising from cells timestamped at days 1, 7, and 28 (corresponding to fetal, neonatal, and adult-derived cells, respectively) could then be tracked by red fluorescent protein expression. Comparing RNA sequencing profiles of day 1 and day 28 ts cells showed that day 1 ts cells were enriched for effector genes, whereas day 28 ts cells were enriched for naïve and late memory genes. In vitro studies also showed that day 1 ts cells divided more quickly and produced more granzyme B and interferon γ immediately upon T cell receptor stimulation when compared with day 28 ts cells.

The authors showed that fetal-derived cells give rise to CD8+ T cells with a preexisting memory phenotype, so-called virtual memory cells. These cells generate long-lived effector cells after exposure to Listeria. Adult-derived CD8+ T cells respond to a Listeria challenge by generating long-lived CD8+ central memory T cells. To explore the basis for this predisposition of fetal-derived cells to develop an effector phenotype, the authors assessed the chromatin landscape of day 1 and day 28 ts cells using assay for transposase-accessible chromatin using sequencing. They found that day 1 ts cells exhibited increased accessibility at genes that promote effector T cell differentiation.

Overall, this study shows that different CD8+ T cells arise from progenitors of different ages. Fetal origin T cells give rise to more long-lived effectors, whereas adult-derived T cells largely generate central memory T cells. One speculation based on this work is that delaying vaccination for some pathogens may more efficiently generate long-lived memory responses.